Microenvironmental Regulation by Fibrillin-1

Sengle, Gerhard; Tsutsui, Ko; R. Keene, Douglas; Tufa, Sara F.; Carlson, Eric J.; Charbonneau, Noe L.; Ono, Robert N.; Sasaki, Takako; Wirtz, Mary K.; Samples, John R.; Fessler, Liselotte I.; Fessler, John H.; Sekiguchi, Kiyotoshi; Hayflick, Susan J.; Sakai, Lynn Y.

doi:https://doi.org/10.1371/journal.pgen.1002425

Microenvironmental Regulation by Fibrillin-1

Sengle, Gerhard; Tsutsui, Ko; R. Keene, Douglas et al.

PLOS Genetics, 2012, 8(1), e1002425

Number of Access:1,361（2025-08-18 12:34 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/71800

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Title	Microenvironmental Regulation by Fibrillin-1
Creator	CreatorName Sengle, Gerhard
	CreatorName Tsutsui, Ko
	CreatorName R. Keene, Douglas
	CreatorName Tufa, Sara F.
	CreatorName Carlson, Eric J.
	CreatorName Charbonneau, Noe L.
	CreatorName Ono, Robert N.
	CreatorName Sasaki, Takako
	CreatorName Wirtz, Mary K.
	CreatorName Samples, John R.
	CreatorName Fessler, Liselotte I.
	CreatorName Fessler, John H.
	NRID 1000050187845 1000050187845 researchmap permalink read0054833 read0054833 Scopus Author ID 7201662709 7201662709 ORCID 0000-0002-6433-1410 0000-0002-6433-1410 CreatorName Sekiguchi, Kiyotoshi
	CreatorName Hayflick, Susan J.
	CreatorName Sakai, Lynn Y.
Description	Sengle G, Tsutsui K, Keene DR, Tufa SF, Carlson EJ, Charbonneau NL, et al. (2012) Microenvironmental Regulation by Fibrillin-1. PLoS Genet 8(1): e1002425. https://doi.org/10.1371/journal.pgen.1002425
Abstract	Fibrillin-1 is a ubiquitous extracellular matrix molecule that sequesters latent growth factor complexes. A role for fibrillin-1 in specifying tissue microenvironments has not been elucidated, even though the concept that fibrillin-1 provides extracellular control of growth factor signaling is currently appreciated. Mutations in FBN1 are mainly responsible for the Marfan syndrome (MFS), recognized by its pleiotropic clinical features including tall stature and arachnodactyly, aortic dilatation and dissection, and ectopia lentis. Each of the many different mutations in FBN1 known to cause MFS must lead to similar clinical features through common mechanisms, proceeding principally through the activation of TGFβ signaling. Here we show that a novel FBN1 mutation in a family with Weill-Marchesani syndrome (WMS) causes thick skin, short stature, and brachydactyly when replicated in mice. WMS mice confirm that this mutation does not cause MFS. The mutation deletes three domains in fibrillin-1, abolishing a binding site utilized by ADAMTSLIKE-2, -3, -6, and papilin. Our results place these ADAMTSLIKE proteins in a molecular pathway involving fibrillin-1 and ADAMTS-10. Investigations of microfibril ultrastructure in WMS humans and mice demonstrate that modulation of the fibrillin microfibril scaffold can influence local tissue microenvironments and link fibrillin-1 function to skin homeostasis and the regulation of dermal collagen production. Hence, pathogenetic mechanisms caused by dysregulated WMS microenvironments diverge from Marfan pathogenetic mechanisms, which lead to broad activation of TGFβ signaling in multiple tissues. We conclude that local tissue-specific microenvironments, affected in WMS, are maintained by a fibrillin-1 microfibril scaffold, modulated by ADAMTSLIKE proteins in concert with ADAMTS enzymes.
Publisher	PLOS
Source Title	PLOS Genetics
Volume (Issue)	8(1)
Page	e1002425
Date of Issued	2012-01
Language	English
Handle URL	https://hdl.handle.net/11094/71800
PISSN	15537390
eISSN	15537404
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1371/journal.pgen.1002425
Access Rights	open access
CopyRight	© 2012 Sengle et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCMI Type	Text
DCTERMS.bibliographicCitation	PLOS Genetics. 2012, 8(1), p. e1002425
DC.title	Microenvironmental Regulation by Fibrillin-1
DC.creator	Sengle, Gerhard
	Tsutsui, Ko
	R. Keene, Douglas
	Tufa, Sara F.
	Carlson, Eric J.
	Charbonneau, Noe L.
	Ono, Robert N.
	Sasaki, Takako
	Wirtz, Mary K.
	Samples, John R.
	Fessler, Liselotte I.
	Fessler, John H.
	Sekiguchi, Kiyotoshi
	Hayflick, Susan J.
	Sakai, Lynn Y.
DC.publisher	PLOS
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2012-01
DC.identifier	https://doi.org/10.1371/journal.pgen.1002425
DC.description	Sengle G, Tsutsui K, Keene DR, Tufa SF, Carlson EJ, Charbonneau NL, et al. (2012) Microenvironmental Regulation by Fibrillin-1. PLoS Genet 8(1): e1002425. https://doi.org/10.1371/journal.pgen.1002425
DCTERMS.abstract	Fibrillin-1 is a ubiquitous extracellular matrix molecule that sequesters latent growth factor complexes. A role for fibrillin-1 in specifying tissue microenvironments has not been elucidated, even though the concept that fibrillin-1 provides extracellular control of growth factor signaling is currently appreciated. Mutations in FBN1 are mainly responsible for the Marfan syndrome (MFS), recognized by its pleiotropic clinical features including tall stature and arachnodactyly, aortic dilatation and dissection, and ectopia lentis. Each of the many different mutations in FBN1 known to cause MFS must lead to similar clinical features through common mechanisms, proceeding principally through the activation of TGFβ signaling. Here we show that a novel FBN1 mutation in a family with Weill-Marchesani syndrome (WMS) causes thick skin, short stature, and brachydactyly when replicated in mice. WMS mice confirm that this mutation does not cause MFS. The mutation deletes three domains in fibrillin-1, abolishing a binding site utilized by ADAMTSLIKE-2, -3, -6, and papilin. Our results place these ADAMTSLIKE proteins in a molecular pathway involving fibrillin-1 and ADAMTS-10. Investigations of microfibril ultrastructure in WMS humans and mice demonstrate that modulation of the fibrillin microfibril scaffold can influence local tissue microenvironments and link fibrillin-1 function to skin homeostasis and the regulation of dermal collagen production. Hence, pathogenetic mechanisms caused by dysregulated WMS microenvironments diverge from Marfan pathogenetic mechanisms, which lead to broad activation of TGFβ signaling in multiple tissues. We conclude that local tissue-specific microenvironments, affected in WMS, are maintained by a fibrillin-1 microfibril scaffold, modulated by ADAMTSLIKE proteins in concert with ADAMTS enzymes.
DC.rights	© 2012 Sengle et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DC.format	71800
citation_title	Microenvironmental Regulation by Fibrillin-1
citation_author	Sengle, Gerhard
	Tsutsui, Ko
	R. Keene, Douglas
	Tufa, Sara F.
	Carlson, Eric J.
	Charbonneau, Noe L.
	Ono, Robert N.
	Sasaki, Takako
	Wirtz, Mary K.
	Samples, John R.
	Fessler, Liselotte I.
	Fessler, John H.
	Sekiguchi, Kiyotoshi
	Hayflick, Susan J.
	Sakai, Lynn Y.
citation_publisher	PLOS
citation_language	English
citation_date	2012-01
citation_journal_title	PLOS Genetics
citation_volume	8
citation_issue	1
citation_firstpage	e1002425
citation_doi	https://doi.org/10.1371/journal.pgen.1002425
citation_public_url	https://hdl.handle.net/11094/71800

Microenvironmental Regulation by Fibrillin-1

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